Xin Sheng, Song Wen, Mao Jiaquan, Hu Peng, Chen Zhong, Liu Jihong, Song Xiaodong, Fang Qian, Cui Kai
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China.
Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China.
Andrology. 2024 Nov 25. doi: 10.1111/andr.13814.
Among erectile dysfunction (ED) caused by metabolic abnormalities, diabetes mellitus-induced ED (DMED) progresses rapidly, manifests with severe symptoms, and shows reduced responsiveness to conventional medications. Hyperglycemia in the corpus cavernosum has been linked to the induction of both ferroptosis and oxidative stress, which are mediated by nuclear factor E2 related factor 2 (Nrf2). Hesperidin (Hes), a flavonoid compound, has been revealed to activate Nrf2 in certain diabetic complications, yet the efficacy of Hes on DMED and the specific mechanism remain unclear.
To elucidate the potential mechanism and efficacy of Hes in regulating Nrf2-mediated ferroptosis and oxidative stress in DMED.
DMED rats were constructed through the intraperitoneal injection of streptozotocin (STZ), partially supplemented with Hes. In parallel, in vitro research utilized human umbilical vein endothelial cells (HUVECs), with glucose addition to simulating a high glucose (HG) environment, and induced with Hes or ML385 (an Nrf2 inhibitor). Penile tissues and HUVECs were harvested for subsequent analyses.
The results of this study indicate that Hes partially reversed the impaired erectile function. The expression of Nrf2, glutathione peroxidase 4 (GPX4), and heme oxygenase-1 (HO-1) in the corpus cavernosum elevated after supplementing with Hes, resulted in an inhibition in ferroptosis and oxidative stress. Moreover, the quantity and function of erectile effector cells were restored, and cavernous fibrosis was ameliorated. In HG-induced HUVECs, Hes ameliorated Nrf2-mediated ferroptosis and oxidative stress, effects which ML385 partially reversed.
Hes exerts a therapeutic effect on DMED rats and a regulatory mechanism on the Nrf2-HO-1/GPX4 axis, concurrently revitalizing endothelial and smooth muscle cells, and diminishing fibrosis. Our study provides robust preclinical evidence for employing Hes in treating DMED.
在由代谢异常引起的勃起功能障碍（ED）中，糖尿病性勃起功能障碍（DMED）进展迅速，症状严重，且对传统药物的反应性降低。海绵体内的高血糖与铁死亡和氧化应激的诱导有关，这两者均由核因子E2相关因子2（Nrf2）介导。橙皮苷（Hes）是一种黄酮类化合物，已发现在某些糖尿病并发症中可激活Nrf2，但Hes对DMED的疗效及具体机制尚不清楚。
阐明Hes调节DMED中Nrf2介导的铁死亡和氧化应激的潜在机制及疗效。
通过腹腔注射链脲佐菌素（STZ）构建DMED大鼠模型，并部分给予Hes。同时，体外研究使用人脐静脉内皮细胞（HUVECs），添加葡萄糖以模拟高糖（HG）环境，并给予Hes或ML385（一种Nrf2抑制剂）诱导。收集阴茎组织和HUVECs用于后续分析。
本研究结果表明，Hes部分逆转了受损的勃起功能。补充Hes后，海绵体内Nrf2、谷胱甘肽过氧化物酶4（GPX4）和血红素加氧酶-1（HO-1）的表达升高，导致铁死亡和氧化应激受到抑制。此外，勃起效应细胞的数量和功能得以恢复，海绵体纤维化得到改善。在HG诱导的HUVECs中，Hes改善了Nrf2介导的铁死亡和氧化应激，而ML部分逆转了这些作用。
Hes对DMED大鼠具有治疗作用，并对Nrf2-HO-1/GPX4轴具有调节机制，同时使内皮细胞和平滑肌细胞恢复活力，并减少纤维化。我们的研究为使用Hes治疗DMED提供了有力的临床前证据。
